Cyclopropa-androstanone compounds



United States Patent 3,308,139 CYCLOPROPA-ANDROSTANONE COMPOUNDS PeterJohn Palmer, Whitton, Twickenham, England, as-

signor to Parke, Davis & Company, Detroit, Mich., a corporation ofMichigan No Drawing. Filed Jan. 15, 1965, Ser. No. 425,930 Claimspriority, application (ir6eat Britain, Feb. 4, 1964,

4 9 4 Claims. (Cl. 260397.4)

This invention relates to novel chemical compounds and means forproducing the same. More particularly, the invention relates to17a-methyl-17fl-hydroxycyclopropa-[2a,3a]-5a-androstan-4-one and estersthereof represented by the formula:

(ID-R (u) -Acyl by reaction with lithium in the presence of liquidammonia, reducing the resultant lower alkanoyl ester of 170:- methyl 173 hydroxycyclopropa [2a,3nc] 5a androstan-4-on'e of formula:

0 -Acyl ICC by means of lithium aluminum hydride, and oxidizing theintermediate 17oz methyl 17B hydroxycyclopropa-[2a,3a]50c-1IldI0Sl1aI1-4-O1 of formula:

with chromium trioxide and sulfuric acid; where acyl represents a loweralkanoyl group of not more than four carbon atoms, preferably an acetylgroup. The reduction of the androstenone starting material is carriedout with at least two equivalents of lithium. The reaction is favored bythe use of an inert solvent such as ether. Following the initialreaction, which is ordinarily complete within about 30 minutes, thereaction mixture is decomposed with an inorganic salt of a weak basewith a strong acid, such as ammonium chloride. The ester product of thereaction (Formula III) can be isolated and purified for purposes of theinvention as a final product or it can be further processed, asindicated, to provide the corresponding hydroxyandrostanone of FormulaI. The reduction of the ester product is carried out with at least 1.5molar equivalents of lithium aluminum hydride in an anhydrous inertsolvent such as ether or tetrahydrofuran. The reaction is convenientlycarried out at room temperature or higher temperature up to the boilingpoint of the reaction mixture. Following the reaction, which isordinarily complete in less than one-half hour, the reaction mixture isdecomposed in an aqueous medium such as water or dilute acid. Theoxidation with chromium trioxide and sulfuric acid is carried out in aninert, watermiscible organic solvent such as acetone, dioxane ortetrahydrofuran. Conveniently, the reaction is run at temperatures inthe range from about 20 to 20 C. The reaction is ordinarily complete ina short period, for example, five minutes at 0 C. Any excess oxidantpresent after the reaction is advantageously decomposed by addition ofan alcohol such as methanol.

Also in accordance with the invention, the process for the production ofcompounds of Formula I where R is a lower alkanoyl group, comprisesreacting Una-methyl- 17,3-hydroxycyclopropa-[2045a]-5a-androstan-4-onewith at least one equivalent of an acylating agent, such as an acylhalide or an acid anhydride, derived from an organic acid containing notmore than four carbon atoms. Conveniently, the acylation is accomplishedby reaction with an acyl halide or an acid anhydride or in two steps byreaction with a lower alkyl Grignard reagent and subsequent reaction ofthe resulting Grignard compound with an acyl halide. The acylation withacyl halide is carried out with a tertiary amine catalyst such aspyridine or triethylamine at temperatures in the range from 0 to 100 C.for periods from about 2 to 24 hours, preferably from 20 to C. for 14 to18 hours. The tertiary amine can serve as a solvent or an inert solventsuch as diethyl ether or benzene may be used. Acyl halides containingnot more than four carbon atoms such as acetyl chloride or propionylchloride are employed for the reaction. The acylation with acidanhydride is carried out Patented Mar. 7, 1967 I 3 with or withoutcatalyst (tertiary amine catalyst such as pyridine or triethylamine) attemperatures in the range from to 150 C. for one to 18 hours, preferablyfrom 115 to 140 C. for two hours. As a solvent, one may use excessanhydride or a tertiary amine or an inert solvent such as benzene ordiethyl ether. The acylatlon with Grignard reagents and acyl halide iscarried out in an inert solvent such as diethyl ether or tetrahydrofuranat temperatures in the range from 0 to 50 C. for one to 18 hours,preferably at to C. for 24 to 48 hours.

The invention also includes the production of the ester compounds ofFormula I where R represents a lower alkanoyl group by reducing acyclopropa-androstenone compound of Formula II with lithium in thepresence of liquid ammonia as indicated above.

The compounds of the invention possess useful pharmacologicalproperties. In particular, when administered by the oral or parenteralroutes, the compounds exhibit significant myotropic activity yet haverelatively low androgenic side effects; hence, they have application asanabolic agents. The compounds are also useful as intermediates for theproduction of other steroids. A preferred anabolic agent of theinvention is l7a-methyl-l7l3-hydroxycyclopropa-[204,3a]-5ot-androstan-4-one.

The cyclopropa-androstenone ester starting materials for the process ofthe invention can beprepared in five steps from2-methylene-17u-methyl-17,8-hydroxyandrost- 4-en-3-one, as follows: thelatter compound is reacted with hydrazine to form the 2a,3a-cyclopropaderivative, the cyclopropa compound is acylated at the 17-hydroxyposition, the resulting ester is hydroxylated at the 4- and 5-positionsby treatment with osmium tetroxide, the resulting diol is converted tothe corresponding SwhydrOXyandrostan-4-one by oxidation with chromiumtrioxide and sulfuric acid, and the latter intermediate is dehydratedwith thionyl chloride in the presence of pyridine to give thecorresponding androst-5-en-4-one.

The invention is illustrated by the following examples.

Example 1 (a) A solution of l7zx-methyl-17B-hydroxycyclopropa-[205,304]-androst-5-en-4-one, acetate ester (5 g.) in ether (100 ml.) isadded over a period of twenty minutes to a solution of lithium (0.5 g.)in liquid ammonia (300 ml.). The mixture is stirred an additional tenminutes, and then ammonium chloride is added in amount sufiicient todecolorize the mixture. The ammonia is removed from the mixture byevaporation and the residue extracted with two SO-ml. portions of ether.The combined ether extract is washed with water, dried and the etherremoved by evaporation. The residual product is17a-methyl-17flhydroxycyclopropa [2a,3oc]-5ot-21I1dIOS't8Jl-4-OI16,acetate ester. The product can be purified by adsorption on alumina,elution with benzene and crystallization from acetone, or it can be useddirectly as an intermediate without further purification. By replacingthe acetate ester starting material in this procedure with an equivalentamount of the corresponding propionate ester one obtains 17cc methyl17/3 hydroxycyclopropa-[2a,3a]-5aandrostan-4-one, propionate ester.

(b) 1704 methyl 17,8 hydroxycyclopropa-[2a,3a]- 5a-androstan-4-one,acetate ester [the product of Example 1(a)] is dissolved in ether (100ml.) and the solution is stirred with lithium aluminum hydride (2.5 g.)for ten minutes at room temperature. The reaction mixture is decomposedby the addition of water (25 ml.) and cold dilute sulfuric acid (1.0 N,150 ml.) and is then extracted with two -ml. portions of ether. Thecombined extract is washed with water, dried and the ether removed byevaporation. The residual product,17a-methyl-17B-hydroxycyclopropa-[2a,3a]-5u-androstan-4-ol, is dissolvedin acetone (500 ml.) and at 0 C. five ml. of Jones Reagent (26.72 g. ofchromium trioxide and 23 ml. of sulfuric acid diluted to 100 ml. withwater) is added over a period of two minutes. After stirring for threeadditional minutes at the same temperature, methanol ml.) is added, andthe solvent is then removed under vacuum. The residual product,17a-methyl-176-hydroxycyclopropa-[2a,3a]-5a-androstan-4-one, is purifiedby adsorption from a benzene solution on neutral alumina (Woelm,activity grade III) and elution with benzene and benzene-petroleum ether(1:1); MP. 189-191 C. following removal of the eluant. The same productis obtained by replacing the acetate ester starting material in thisprocedure with an equivalent amount of the corresponding propionateester.

The preparation of ester starting materials for the above procedure isillustrated by the synthesis of the acetate ester described as follows:hydrazine hydrate (10 ml.) is added to diethylene glycol ml.) and thesolution heated to 180 C. under nitrogen.2-methylene-17amethyl-l7B-hydroxyandrost-4-en-3-one (5 g.) is added andthe solution is heated at reflux for 30 minutes. A solution of sodium (2g.) in diethylene glycol (50 ml.) is added. The reaction temperature isincreased to 210 C. and excess hydrazine hydrate removed bydistillation. The solution is then heated at reflux for four hours andis finally cooled and poured into 500 ml. of water. The mixture isextracted with ether, dried and concentrated. The residual product,17a-methyl-cyclopropa-[2043a]- androst-4-en-17B-ol, is purified byadsorption on alumina, elution with benzene and crystallization fromacetone, M.P. 121123 C. A solution of the androstenol (1 g.) in pyridine(5 ml.) and acetic anhydride (5 ml.) is refluxed for three hours, thencooled and poured into water (50 ml.). The mixture is extracted withether, and the extract is washed in turn with dilute acid, water, dilutebase, and water and then concentrated. The product, 170v methylcyclopropa-[2a,3x]-androst-4-en-l7fl-ol, acetate ester (M.P. 7880 C.from acetone), is dissolved in the amount of 871 mg. in ether (15 ml.)together with osmium tetroxide (1 g.) and pyridine (1 ml.) and allowedto stand overnight at room temperature. The resulting mixture isdissolved in methylene chloride and the solution is saturated withhydrogen sulfide. The mixture is filtered, and the filtrate is washedwith dilute acid, water, dilute base and water and then is dried andconcentrated. The residual pro-duct,17zx-methyl-17fl-acetoxy-4a,5a-dihydroxy-cyclopropa-[2a,3a]-androstane,is dissolved in acetone (50 ml.) at 0 to 5 C. One ml. of Jones Reagent[chromium trioxide (26.72 g.) and sulfuric acid (23 ml.) diluted to 100ml. with water] is added with stirring to this solution over a period ofone minute. The mixture is stirred four minutes longer and is thendiluted with methanol (25 ml.). The solution is concentrated to 10 ml.,diluted with water (50 ml.) and extracted with ether. The extract iswashed with water, aqueous sodium bicarbonate and water, and is thendried and concentrated. The residual product,l7u-methyl-l7fl-acetoxy-5a-hydroxycyclopropa-[2a,3a]-androstan-4-one, ispurified by adsorption on alumina, elution with benzene, andcrystallization from aqueous methanol, M.P. 201-203 C. Thionyl chloride(0.5 ml.) is added dropwise to a stirred solution of the androstanone(0.5 g.) in pyridine (10 ml.)

- teria-l, 17a methyl-17B-hydroxycyclopr-opa-[2a,3a]-androst-5-en-4-one, acetate ester; M.P. 159 C. from acetone.

Example 2 A solution of 1.0 g. of17'a-methyl-17,8-hydroxycyclopropa-[2a,3 x]-5a-androstan-4-one in 5 ml.of pyridine and 5 ml. of acetic anhydride is heated at reflux for 3hours, and is then cooled and poured into 50 ml. of water. The mixtureis extracted with two 25-ml. portions of ether. The combined etherextract is washed sue where R is a member of the group consisting ofhydrogen and lower alkanoyl.

2. 17m methyl 17fl-hydroxycyclopropa-[2a,3a]-5uandrostan-4-one.

3. 17oz methyl 1718-hydroxycyclopropa-[2a,3a1-5aandrostan-4-one, acetateester.

4. Process for the production of17a-methyl-17/3-hydroxycyclopropa-[2a,3a]-5u-androstan-4-one, whichcomprises reducing a lower alkanoyl ester of17a-methyl-l7flhydlroxycyclopropa-[2a,3a]-andr0st-5-en-4-o'ne of formua:

O -Acyl by reaction with lithium in the presence of liquid ammonia,reducing the resultant lower alkanoyl ester of 17oz methyl17fl-hydroxycyclopropa-[2a,3a]dot-androstan-4-one of formula:

O-Acyl orn 10 I H x H a by means of lithium aluminum hydride, andoxidizing the intermediate 17a methyl 17fl-hydroxycyclopropa-[2a,3a]-5a-androstan-4-o-l of formula:

/C H r g n on with chromium trioxide and sulfuric acid; where acylrepresents a lower alkanoyl group of not more than four canbon atoms.

References Cited by the Examiner Barton et a1.: Chem. Soc. Jour., pp.3045-51 (1954). Loewenthal: Tetrahedron, vol. 6, pp. 269-303, June 1959,pp. 299301.

ELBERT L. ROBERTS, Acting Primary Examiner.

HENRY FRENCH, Assistant Examiner,

1. CYCLOPROPA-(2A,3A)-5A-ANDROSTAN-4-ONE COMPOUNDS OF THE FORMULA: